Reiner P B, Kamondi A
Kinsmen Laboratory of Neurological Research, Department of Psychiatry, University of British Columbia, Vancouver, Canada.
Neuroscience. 1994 Apr;59(3):579-88. doi: 10.1016/0306-4522(94)90178-3.
Antihistamines, more formally termed H1 receptor antagonists, are well known to exert sedative effects in humans, yet their locus and mechanism of action in the human brain remains unknown. To better understand this phenomenon, the effects of histamine upon human cortical neurons were studied using intracellular recordings in brain slices maintained in vitro. Bath application of 50 microM histamine induced a depolarization which could be attributed to reduction of a background voltage-independent "leakage" potassium current: the depolarization was associated with an increase in apparent input resistance, under voltage clamp its reversal potential approximated the potassium reversal potential, and the histamine-induced current exhibited little voltage dependence. The pharmacology of the histamine-induced depolarization of human cortical neurons was studied by use of both agonists and antagonists. Depolarizing responses were blocked by the H1 antagonist mepyramine, but not by the H2 antagonist cimetidine nor the H3 antagonist thioperamide. The H3 receptor agonist R-alpha-methyl-histamine did not mimic the effects of histamine. Thus, histamine depolarizes human cortical neurons via action at an H1 receptor. These effects of neuronal histamine upon cortical neurons are likely to affect synaptic transmission in several ways. The depolarization per se should increase the likelihood that excitatory synaptic potentials will evoke an action potential. The increase in whole-cell input resistance evoked by H1 receptor activation should make the cell more electrotonically compact, thereby altering its integrative properties. We hypothesize that these mechanisms would allow histamine, acting at cortical H1 receptors, to enhance behavioral arousal. During waking when histamine release is highest, blockade of H1 receptors by systemically administered H1 receptor antagonists would be sedating.
抗组胺药，更正式地称为H1受体拮抗剂，众所周知会在人体中产生镇静作用，但其在人脑中的作用位点和作用机制仍不清楚。为了更好地理解这一现象，利用体外培养的脑片进行细胞内记录，研究了组胺对人皮质神经元的影响。在浴槽中施加50微摩尔组胺可诱导去极化，这可归因于背景电压非依赖性“泄漏”钾电流的减少：去极化与表观输入电阻的增加相关，在电压钳制下其反转电位接近钾反转电位，且组胺诱导的电流几乎没有电压依赖性。通过使用激动剂和拮抗剂研究了组胺诱导的人皮质神经元去极化的药理学。去极化反应被H1拮抗剂美吡拉敏阻断，但未被H2拮抗剂西咪替丁或H3拮抗剂硫代哌啶阻断。H3受体激动剂R-α-甲基组胺不能模拟组胺的作用。因此，组胺通过作用于H1受体使人类皮质神经元去极化。神经元组胺对皮质神经元的这些作用可能会以多种方式影响突触传递。去极化本身应增加兴奋性突触电位诱发动作电位的可能性。H1受体激活引起的全细胞输入电阻增加应使细胞在电紧张方面更紧密，从而改变其整合特性。我们假设这些机制将使作用于皮质H1受体的组胺增强行为觉醒。在组胺释放最高的清醒期间，全身给予H1受体拮抗剂阻断H1受体将产生镇静作用。
